The present invention relates to a method of amidating carboxylic acids with an aromatic amine in the presence of a boron containing compound, such as boric acid, and, optionally, a 2-pyridinylamine.
Carboxamides, such as those disclosed in U.S. Pat. No. 5,773,647, have been found to be highly effective as delivery agents for active agents, particularly for oral administration of active agents.
Generally, carboxamides are prepared by an amidation reaction between a carboxylic acid and an amine. The carboxylic acid is typically converted into an electrophilic intermediate, usually an acid chloride. The acid chloride is then reacted with the amine in the presence of an activating agent. Many acid chlorides, however, are unstable or are not compatible with other functional groups present in the acid or amine. Therefore, protection and deprotection steps must be performed in order to stabilize the intermediate and protect various functional groups. This dramatically increases the cost of preparing the carboxamide.
Carboxamides may also be formed by reacting a carboxylic acid with 1-hydroxybenzotriazole in the presence of coupling agents, such as 1,3-dicyclohexylcarbodiimide (DCC) and ethylene dichloride (EDC). This method, however, forms urea byproducts which are often difficult to remove, especially in large scale preparations.
Boron trifluoride etherate, trialkylboranes, trialkoxyboranes, catecholborane, and arylboronic acids have also been reported to catalyze amidation reactions of carboxylic acids. See, for example, Trapani, G. et al., Synthesis, 1013 (1983); Tani, J. et al., Synthesis, 714 (1975); Pelter, A. et al., Tetrahedron, 26:1539 (1970); Collum, D. B. et al., J. Org. Chem., 43:4393 (1978); Ishihara, K. et al., J. Org. Chem., 61:4196 (1996).
Therefore, there is a need for an inexpensive and simple method for preparing carboxamides from carboxylic acids.
The present invention provides an inexpensive one-step method for preparing an aromatic carboxamide, such as a phenyl substituted carboxamide by reacting an aromatic amine (e.g. a phenylamine) and a carboxylic acid (e.g. an alkanoic acid or ester thereof) in the presence of a boron containing compound (e.g. boronic acid or boric acid) and, optionally, a chelating agent (e.g. a 2-pyridinylamine).
A preferred embodiment is a method for preparing a carboxamide having the formula 
where
R1, R2, R3, R4, and R5 are independently hydrogen, xe2x80x94OH, xe2x80x94Oxe2x80x94R7, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, carboxyl, substituted or unsubstituted alkoxycarbonyl, halogen, nitrile, xe2x80x94OC(O)CH3, xe2x80x94SO3H, or xe2x80x94NR13R14;
R6 is C1-C12 alkyl;
R6 is optionally substituted with one or more alkenyl, alkoxycarbonyl, carboxyl, xe2x80x94OH, or halogen;
R7 is hydrogen, alkyl, or aryl; and
R13 and R14 are independently hydrogen, C1-C4 alkyl, or oxygen.
The method comprises the step of reacting (a) an aromatic amine having the formula 
with (b) an acid having the formula R6xe2x80x94COOH in the presence of a boron containing compound and, optionally, a chelating agent to form the carboxamide, where R1, R2, R3, R4, R5, and R6 are defined as above. A preferred acid has the formula 
where R15 is a C1-C12 alkyl and R16 is an alkyl (e.g. a C1-C3 alkyl). A preferred chelating agent is a 2-pyridinylamine. Preferably the boron containing compound is boric acid and the 2-pyridinylamine is 2-amino-5-picoline. The carboxamide may be subsequently modified to include a carboxylic acid terminal on the R6 group, if it does not already have such a terminal.
A more preferred embodiment is a method for preparing a carboxamide having the formula: 
where
R1, R2, R3, R4, and R5 are independently hydrogen, xe2x80x94OH, xe2x80x94Oxe2x80x94R7, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, carboxyl, substituted or unsubstituted alkoxycarbonyl, halogen, nitrile, xe2x80x94OC(O)CH3, xe2x80x94SO3H, or xe2x80x94NR13R14;
R7 is hydrogen, alkyl, or aryl;
R13 and R14 are independently hydrogen, C1-C4 alkyl, or oxygen; and
R15 is C1-C12 alkyl.
The method comprises the steps of (i) reacting (a) an aromatic amine having the formula 
with (b) an acid having the formula 
where R15 is a C1-C12 alkyl and R16 is an alkyl (e.g. a C1-C3 alkyl), in the presence of a boron containing compound and, optionally, a chelating agent to form an intermediate having the formula 
where R1, R2, R3, R4, R5, R15, and R16 are defined as above; and (ii) hydrolyzing the intermediate to form the final carboxamide. Preferably, the boron containing compound is boric acid and the chelating agent is a 2-pyridinylamine, such as a 2-amino-5-picoline.
The alkyl, alkenyl, alkoxy and aryl groups of R1, R2, R3, R4, and R5 may be substituted with, for example, xe2x80x94OH, F, and alkyl and aryl groups. R1, R2, R3, R4, and R5 may be C1-C18 alkyl, C2-C18 alkenyl, C1-C18 alkoxy, or (C1-C18 alkoxy)carbonyl. For example, R1, R2, R3, R4, and R5 maybe C1-C4 alkyl, C2-C4 alkenyl, or C1-C4 alkoxy. The alkoxycarbonyl group of R1, R2, R3, R4, and R5 may be substituted with, for example, alkyl groups (such as C1-C4 alkyl).
Suitable boron containing compounds include, but are not limited to, boronic acids, such as those having the formula R8xe2x80x94B(OH)2, where R8 is xe2x80x94OH; aryl; C1-C8 alkyl, optionally substituted with C1-C3 alkyl; or a polymer. Preferably, the boron containing compound is boric acid, i.e., R8 is xe2x80x94OH.
Without being bound by any theory, the inventors believe that boric acid forms a reactive complex with the carboxylic acid to form an acyloxyboron intermediate and water. After the water is removed, the acyloxyboron intermediate readily reacts with the aromatic amine to afford the desired carboxamide and regenerate boric acid, the amidation catalyst.
The chelating agent may be any chelating agent known in the art. Suitable chelating agents include, but are not limited to, electron donating chelating agents. Preferred chelating agents include, but are not limited to, 2-pyridinylamines. Suitable 2-pyridinylamines include, but are not limited to, those having the formula 
where R9, R10, R11, and R12 are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstitued aryl. The alkyl and aryl groups of R9, R10, R11, and R12 may be substituted with, for example, alkyl (such as C1-C4 alkyl) and aryl groups. Preferably, the 2-pyridinylamine is 2-amino-4-picoline, 2-amino-5-picoline, 2-amino-6-picoline, 2-amino-4,6-dimethylpyridine, or any combination of any of the foregoing. More preferably, the 2-pyridinylamine is 2-amino-5-picoline.
The boron containing compound and, optionally, the 2-pyridinylamine catalyze the reaction between the aromatic amine and the acid. Without being bound to any theory, the inventors believe that the boron containing compound forms a complex with the 2-pyridinylamine. This complex may react with the acid to form an acyloxyboron intermediate which can readily react with the aromatic amine to yield the carboxamide.
The reaction may be performed at a temperature of from about 20xc2x0 C. to about 200xc2x0 C. The reaction may be performed in the solid or liquid phase.
The aromatic amine and acid are preferably dissolved in a solvent. Suitable solvents include, but are not limited to, aromatic solvents, such as benzene, xylene, mesitylene, and toluene; hydrocarbon solvents, such as hexane and octane; and any combination of any of the foregoing. Preferably, the solvent is toluene.
Water which is formed as a byproduct from the reaction of the aromatic amine and the acid is preferably removed during the reaction, such as, with a Dean-Stark separator.
The reaction is typically performed at atmospheric pressure. Preferably, the reaction is carried out under an inert gas blanket, such as nitrogen or argon.
The molar ratio of aromatic amine to the acid preferably ranges from about 1:1 to about 1:1.1 and more preferably from about 1:1 to about 1:1.03. The molar ratio of boron containing compound to 2-pyridinylamine preferably ranges from about 10:1 to about 1:5 and more preferably is about 1:1. The molar ratio of boron containing compound or 2-pyridinylamine to aromatic amine or acid preferably ranges from about 1:100 to about 1:1 and more preferably ranges from about 1:50 to about 1:4.
Generally, the reaction mixture contains from about 0.1 to about 4 moles of aromatic amine, from about 0.1 to about 4 moles of the acid, and from about 0.001 to about 4 moles of boron containing compound per liter of reaction mixture. The reaction mixture may optionally contain from about 0.001 moles to about 8 moles of 2-pyridinylamine per liter of reaction mixture. Preferably, the reaction mixture contains about 0.5 moles of aromatic amine per liter of reaction mixture.
The reaction may be performed by refluxing a mixture of the aromatic amine and the acid in a solvent and in the presence of the boron containing compound and 2-pyridinylamine. Preferably, the mixture contains toluene as a solvent. Typically, refluxing is performed at a temperature of from about 80 to about 150xc2x0 C. and preferably at about 110xc2x0 C. Typically, the mixture is refluxed for 1 to 16 hours, depending on the starting materials.
The carboxamide may be purified by any method known in the art. For example, the carboxamide may be purified by recrystallization or by fractionation on one or more solid chromatographic supports, alone or linked in tandem. Suitable recrystallization solvent systems include, but are not limited to, acetonitrile, methanol, and tetrahydrofuran. Fractionation may be performed on a suitable chromatographic support such as alumina, using methanol/n-propanol mixtures as the mobile phase; reverse phase chromatography using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water or an appropriate buffer as the mobile phase. When anion exchange chromatography is performed, preferably a 0-500 mM sodium chloride gradient is employed.
The carboxamide may be subsequently modified to include a carboxylic acid terminal on the R6 group, if it does not already have such a terminal. This may be done by any method known in the art. For example, if the acid used in the reaction has the formula 
the carboxamide may be hydrolyzed to remove the R16 group and leave a carboxylic acid group on the carboxamide. Hydrolysis may be performed by any method known in the art, such as by reacting the carboxamide (e.g. the intermediate carboxamide discussed above) with sodium hydroxide.